the environment for mentoring and career development of numerous young clinician-scientists, including 2 of our current project leaders, Drs. Ivy and Kinsella. In the recent past, our NIH SCOR program has further served as an important resource for ongoing NIH T32 training programs in pediatric pulmonary medicine (Dr. Abman;PI) and cardiovascular bioengineering (Dr. Shandas;PI). Despite some successes, however, our current approach to develop and sustain clinician-scientists for careers in translational research in pulmonary hypertension has been limited by the lack of a more formal trainingprogram in clinical research. Diverse training approaches must bedeveloped, in addition toT32 training programs,to better train translational research scientists. Also, there has been a clear lag in training for the applications of newly expanded fields, such as genetics, genetic epidemiology, outcomes research, clinical trial design, drug development, and other areas, especially as applied to pediatric pulmonary vascular disease. Due to the diverse backgrounds of our investigators and the highly-interactive nature of our group, our current NIH SCCOR application provides an opportunity to better utilize the faculty and young investigators to enrich the educational and training aspects PHS 398/2590 (Rev.09/04) Continuation Format Page 425 Principal Investigator/Program Director (Last, First, Middle): STENMARK, Kurt R. of the program. Thus, we propose to develop a Clinical Research Skills Development Core (CRSDC) to the SCCOR program, in order to meet these challenges. The CRSDC will incorporate these philosophies in its approach to training clinical investigators in pediatric pulmonary hypertension. This training program is characterized by diverse and strong laboratory and extensive clinical research opportunities. This program emphasizes the important links between "bench and bedside" through active collaborations among diverse faculty and programs in the Departments of Pediatrics, Genetics and Biometrics, the Pediatric Pulmonary Medicine and Pediatric Critical Care sections, MDs and PhD scientists, and clinical and laboratory investigators. Details of this program are presented below. B. How the Clinical Research Skills Development Core relates to current research programs and training activities in pulmonary vascular biology at UCHSC: Training programs must be sufficiently structured to prepare and enable the clinician-investigator for a sustainable career in translational research. In this SCCOR grant, we propose to establish the Clinical Research Skills Development Core (CRSDC) as a new educational program in translational research to address these needs. The CRSDC will achieve this goal by providing a blend of formal courses and close mentoring, and by encouraging high quality, multidisciplinary interactions. The overall goal of the CRSDC is to develop a more formal educational and training program in pediatric pulmonary hypertension, which can bring together the strengths of highly collaborative, multidisciplinary investigators, in order to expand our ability to better train young clinician-scientists in translational research. We have outlined a plan to develop new seminars, workshops and training approaches to disease- and patient- oriented research that incorporates experienced investigators from diverse fields. With rapid advances in genetics and genomics, proteomics, outcomes research, and related fields, we plan to bring together major leaders in these fields from within our institution and from other academic health centers. The addition of the CRSDCwill provide a formal structure to enhance interactions and training opportunities, which will lead to highly-skilled clinical investigators who can better apply genetics and genetic epidemiology to pediatric pulmonary vascular disease. As outlined in the proposal, we plan to provide rigorous training structure to bring together clinician- scientists with leaders in health outcomes research, clinical trial design, clinical physiology, bioinformatics and other fields. To further enhance the training atmosphere, we plan formal workshops in scientific integrity and ethics, communication skills, mentorship, career development, and other critical topics. This program will be coordinated by Dr. Steven Abman, who has extensive experience with mentorship and training as Director of the Pediatric Heart Lung Center and the PI of the NIH T32 Program in pediatric pulmonary medicine. Hewill work closely with Dr. Kurt Stenmark, the Project Pis and collaborating scientists to develop this Core program. In this section, we present our current resources and environment at TCH and the University of Colorado Health Sciences Center, and how the program will relate to other programs on campus. The NIH SCCOR program on lung vascular disease in infants and children and the Clinical Research Skills Development Core Program will be conducted at various locations and institutions that are affiliated within the University of Colorado Health Sciences Center system. Clinical care and research activities for the specific SCCOR projects and related studies will be conducted at two Level 3 neonatal intensive care nurseries: the Newborn Center at The Children's Hospital, and the Intensive Care Nursery of the University Hospital. The Newborn Center is a 20-bed unit offering the highest level of care for critically ill newborns in the Rocky Mountain Region. There were 657 admissions in 2004. The Intensive Care Nursery at the University Hospital is a 28-bed unit with 718 admissions in 2004. Educational and clinical research collaboration occurs at both institutions with the closely affiliated High Risk Obstetrical Service. This long- standing (>30 years) and extremely collaborative effort between services has resulted in the ability to recruit and enroll large numbers of patients into clinical studies. It is important to note that over the past 4-year period (2001-2004), 536 newborns were admitted to these units with a birth weight between 500- 1250grams. It is these infants that will form the core of the clinical research to be performed. All other clinical care and research projects will be conducted throughout The Children's Hospital (TCH), including activities of the Pediatric Heart Lung Center (PHLC) Clinic and its Pulmonary Hypertension Program. PHS 398/2590(Rev. 09/04) Continuation Format Page 426 Principal Investigator/Program Director (Last, First, Middle): STENMARK, Kurt R. within the outpatient clinic, Pediatric Intensive Care Unit, Cardiac Intensive Care Unit and other sites within TCH. The Pediatric Heart-Lung Center was initiated by Dr. Abmanas a multidisciplinary group of clinicians from various pediatric subspecialties, including neonatologists, pulmonologists, cardiologists, intensivists, respiratory therapists, clinical nurse specialists, statisticians and epidemiologists, who work together to facilitate the design and execution of clinical trials in patients with pulmonary hypertension (Fig1). Many of its members are also active in translational bench research. The PHLC has made it possible for the University of Colorado to lead several large multicenter or single center clinical trials, including studies on the effects of inhaled NO in term neonates with severe PPHN, preterm newborns, older infants and children with acute respiratory failure, congenital heart disease, and others. The PHLC has provided training and educational opportunities for post-doctoral fellows andtransitional faculty, including 5 current K08 and 2K23 awardees. The PHLC has organized regular (weekly) laboratory research conferences for laboratory and clinical investigators on the Fitzsimons campus of UCHSC. In addition, regular conferences on clinical topics (thePHLC Clinical Research Conference) are held twice monthly at TCH, which provides opportunities for translational research in progress sessions and topical presentations for investigators involved in clinical research. Speakers from this past year are included in the Appendix. ?. 1;the Pediatric Heart Lung Center.UCHSC NEONATOLOGY& CARDIOLOGY OBSTETRICS-GYNECOLOGY \ PULMONARY >FEDIATRICHEART ALCARE LIUNG CENTER CLINICAL CARE Inhaled NitricOxide Program -Inpatient Home iNOTherapy Pubnonaty Hypertension Clinic Acute Respiratory Distress Syndrome BPD Follow-up Program ECMO High Frequency Oscillatory Ventilation Neonatal transport Infant Pulmonary Function Testing CLINICAL RESEARCH >SingleCenterStudies . eg, iNO/CF >Randomized Multicenter Trials . Prevention ofBPD . ARDS Therapy >Industry Related Studies LABORATORY RESEARCH 1 1 PHLCLcb Perinatal Research UCHSC Facility, Fitzsimons >Rodent Models >Perinatal ^ Lung Explants Studiesand >Cell Culture Physiology >Molecular >IjthPntcricraim Biology EDUCATION &TRAINING >Symposia >Case Conferences >Extramural Conferences >Lab Mentoring for Fellows, Residents, Students & VisitingFaculty >MH Training Program The PHLC Clinical Research Program has led to many new projectsfrom investigators normally not involved in the pulmonary circulation. These include collaborations with gastroenterology (porto-pulmonary hypertension), bone marrow transplant service (severe pulmonary hypertension in recipients), the cystic fibrosis team (role of pulmonary vascular disease in exercise intolerance in patients with advanced CF lung disease), and hematology (pulmonary hypertension in sickle cell anemia). Most importantly, the PHLC originated a strong clinical program in pulmonary hypertension, makingTCH a major referral center for pediatric pulmonary hypertension patients from throughout the country. This program is currently led by Dr. Dunbar Ivy (SCCOR Project #3 co-investigator), and provides a multi- PHS 398/2590 (Rev. 09/04) Continuation Format Page 427 Principal Investigator/Program Director (Last, First, Middle): STENMARK, Kurt R. disciplinary team of physicians, 2 pediatric nurse practitioners, 2 registered nurses and a respiratory therapist. The Pulmonary Hypertension Program receives referrals largely from the Rocky Mountain Region, but increasingly from the entire U.S. Currently, more than 200 patients are followed in this program, including patients with moderate to severe pulmonary hypertension from diverse etiologies. The program receives an average of 50-80 new referrals annually. This group provides consults throughout the hospital, as well as outpatient services. In addition, because of its research mission and its need for state-of-the-art hemodynamic assessment, the program has integrated Dr. Shandas, a flow-dynamics expert, into the program. Dr. Shandas has a joint appointment in the Bioengineering Department at the University of Colorado Boulder. This working relationship brings PhD students and post-docs into the Program and adds a dimension not previously available at The Children's Hospital. Although relatively new, the Pulmonary Hypertension program has demonstrated an ongoing commitment to research. It is an active participant in many pharmaceutical clinical trials related to evaluating the efficacy of bosentan, iloprost, and sildenofil. In addition, the program has had an extensive investigator driven longitudinal protocol in place for the last 6 years examining responses to therapy, quality of life, anthropometries and various blood markers in patients with pulmonary hypertension. In addition to clinical and laboratory research, the PHLC is actively involved in cross-disciplinary teaching of fellows from each of these programs, as well as residents from the Department of Pediatrics. Educational programs include 3 symposia each year, which include: ECMO therapy (in the fall);acute respiratory therapy and ventilator management (winter);and novel therapies of cardiopulmonary diseases (spring). Each session involves morning lectures and discussions in the auditorium at TCH, followed by an animal practicum at the Perinatal Research Facility, in which trainees are provided a "hands on" experience with the application of these therapies (ECMO, high frequency oscillatory ventilation, liquid ventilation and inhaled NO use) in instrumented fetal or neonatal lambs. These sessions included direct physiologic assessments of hemodynamics, gas exchange and related measurements. This provides early exposure to residents and trainees to whole animal physiology, and helps them begin to think about issues in clinical physiology as well. The PHLC also sponsors quarterly journal club sessions that cover multidisciplinary problems in cardiopulmonary medicine. Thus, the PHLC provides a model through which many of the goals fo this Core program can be followed. This program exemplifies the cross-talk between basic and clinical scientists, or linkage of "bench and bedside" investigators, which provides an environment that promotes clinical investigation in a scientific setting, and stimulates novel approaches toward cardiopulmonary diseases in the neonate and older child and career development. Through newly-developed collaborations with Dr. Richard Spritz in the Departments of Pediatrics and Molecular Biology and Genetics, and Head of the Human Medical Genetics Program, we will be able to markedly extend our training and research in genetics, especially as applied to pediatric pulmonary hypertension. The Human Medical Genetics Program includes an extensive laboratory and training program with state-of-the-art approaches to genetic analysis. The program is based on the Fitzsimons campus of the UCHSC, and neighbors the PHLC laboratory. In addition, Dr. Jill Morris, Head of Genetic Epidemiology, is based within the Department of Biometrics and Preventive Medicine on the UCHSC main campus. The basic studies proposed in the SCCOR grant (Projects#4 and #5), will be carried out at the main UCHSC and Fitzsimons campus, as well as at the National Jewish Medical and Research Center. Dr. Stenmark leads the Developmental Lung Biology Laboratory. This is a fully equipped laboratory with over 3,000 sq. ft. of space, which is fully equipped to perform cellular and molecular studies related to lung and lung vascular development. In addition to Dr. Stenmark, Frid and Grayck, there are several other investigators in the laboratory with ongoing research projects related to the developing lung circulation. Importantly the Developmental Lung Biology Laboratory is adjacent to the Pediatric Cardiology Division Laboratories. The Cardiovascular Pulmonary (CVP) Research Laboratory, headed by Dr. Ivan McMurtry, Professor of Medicine and a member of the SCCOR advisory committee, has been an active